As is well known in the art, atherosclerosis is a very important factor causative of various cardiovascular diseases, and extensive and intensive studies have been conducted with a view to suppression of the progress of atherosclerosis or regression of atherosclerosis. In particular, the efficacy of a drug for lowering cholesterol in the serum or arterial wall is recognized. However, an ideal drug having a significant clinical effect and less liable to occurrence of an adverse effect has not been realized in the art.
In recent years, it has become apparent that the accumulation of a cholesterol ester in an arterial wall is an important factor causative of the progress of atherosclerosis. Therefore, a lowering in the cholesterol level in the blood is useful for suppression of the progress of atherosclerosis and regression of the atherosclerosis.
Cholesterol in foods is esterified in tunica mucosa intestini tenuis and then incorporated as chylomicron in the blood. It is known that ACAT plays an important role in the formation of a cholesterol ester in the tunica mucosa intestini tenuis or arterial wall. Therefore, it is considered that the inhibition of ACAT in the tunica mucosa intestini tenuis and the prevention of the esterification can prevent the absorption of the cholesterol, and the cholesterol level of the blood can be lowered.
In the arterial wall, the cholesterol is accumulated as a cholesterol ester. Therefore, it is expected that the inhibition of ACAT in the arterial wall can effectively prevent the accumulation of the cholesterol ester.
Thus, an ACAT inhibitor is considered likely to become a drug useful for treating hyperlipidemia and atherosclerosis through the prevention of the cholesterol in intestinum tenue and the accumulation of the cholesterol in the arterial wall.
For example, urea derivatives (see, for example, J. Med. Chem., vol. 29, 1131 (1986) and Japanese Unexamined Patent Publication (Kokai) Nos. 63-316761 (which corresponds to EP-A-293880 and 1-93569 (which corresponds to EP-A-297610)) and amide derivatives (see, for example, Japanese Examined Patent Publication (Kokoku) No. 63-54718 (which corresponds to U.S. Pat. No. 4,296,240 and U.S. Pat. No. 4,297,349) and Japanese Unexamined Patent Publication (Kokai) No. 63-253060 (which corresponds to U.S. Pat. No. 4,716,175) have hitherto been reported as the above-mentioned ACAT enzyme inhibitor. In all the above-mentioned compounds, although the aromatic nucleus is bonded to a nitrogen atom of a urea or amide portion directly or through an alkylene group, no compound is disclosed wherein a benzoxazole condensed ring, that is, benzoxazole or 2,3-dihydrobenzofuran ring, is directly bonded to a nitrogen atom of the urea or amide portion.
It is known that some compounds wherein benzoxazole or 2,3-dihydrobenzofuran ring is directly bonded to a nitrogen atom of a urea or amide portion can be used as an intermediate for synthesizing drugs, insecticides, vermifuges, bacteriocides for agriculture and gardening, herbicides, photographic materials, etc. However, it is unknown whether or not they have an ACAT inhibitory activity. Examples of the former compound known in the art include compounds for use as an insecticide, wherein a substituted arylcarbonyl group is bonded to one of the nitrogen atoms of a ureylene group bonded to the benzene ring (see Japanese Unexamined Patent Publication (Kokai) No. 64-42474); compounds for use as a vermifuge, wherein a substituted or unsubstituted phenylamide group ##STR3## is bonded to the benzene ring (see Canadian Patent No. 842258); calcimycin (A-23187) known as Ca ionophore and derivatives thereof (see J. Am. Chem. Soc., 104, 1436 (1982); and Japanese Unexamined Patent Publication (Kokai) No. 62-26283 (which corresponds to Derwent Abstract 87-74940)) and several derivatives for use as an optomagnetic material and a heat-resistant material (see Journal of The Society of Organic Synthetic Chemistry, vol. 29, p. 717; and Japanese Examined Patent Publication (Kokoku) No. 64-53303 (which corresponds to U.S. Pat. No. 4,400,294)). Examples of the latter compound known in the art include compounds for use as a herbicide, wherein a chloroacetamide group is bonded to the benzene ring (see Japanese Patent Unexamined Patent Publication (Kokai) No. 60-109585 (which corresponds to Derwent Abstract 85-181198)); compounds for use as a bacteriocide for agriculture and gardening, wherein a substituted phenylamide group is bonded to the benzene ring (see Japanese Unexamined Patent Publication (Kokai) No. 60-215680 (which corresponds to Derwent Abstract 85 -307995)); compounds for use as a starting compound for a pigment, wherein an acetylacetamide group is bonded to the benzene ring (see Japanese Examined Patent Publication (Kokoku) No. 47-7715 (which corresponds to U.S. Pat. No. 3,634,462)); compounds for use as a herbicide, wherein a substituted aryloxyisopropylamide group is bonded to the benzene ring (see Japanese Unexamined PCT Patent Publication (Kohyo) No. 61-501991 (which corresponds to WO-A-86-2642 and EP-A-199794)); compounds for use as an antiallergic drug, wherein a tetrazole group is located as an indispensable group at the 2-position and a substituted phenylamide group is bonded to the benzene ring (see Japanese Unexamined Patent Publication (Kokai) No. 2-138242 (which corresponds to U.S. Pat. No. 4,780,469, U.S. Pat. No. 4,847,257 and U.S. Pat. No. 4,939,141)); compounds for use as an analgesic, wherein an acetamide group is bonded to the benzene ring (see Spanish Patent No. 512355); compounds for use as a herbicide, wherein a methyl or cyclopropyl group is bonded to one nitrogen atom of a ureylene group bonded to the benzene ring (see Canadian Patent No. 117860); and compounds for use as a photosensitive material for silver halide color photography, wherein a substituted alkylamide group or a substituted phenylamide group is bonded to the benzene ring (see Japanese Unexamined Patent Publication (Kokai) Nos. 61-250642 (which corresponds to Derwent Abstract 86-335324) and 61- 233742 (which corresponds to Derwent Abstract 86-315479)). The above-described prior art documents are, however, silent on the fact that benzoxazole or 2,3-dihydrobenzofuran derivatives, including the above-described known compounds, have an ACAT inhibitory activity.